Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1

Abstract

Transcription, splicing, and translation are potentially coordinately regulatable in a temporospatial-dependent manner, although supporting experimental evidence for this notion is scarce. Yeast two-hybrid screening of a mammary gland cDNA library with human p21-activated kinase 1 (Pak1) as bait identified polyC-RNAbinding protein 1 (PCBP1), which controls translation from mRNAs containing the DICE (differentiation control element). Mitogenic stimulation of human cells phosphorylated PCBP1 on threonines 60 and 127 in a Pak1-sensitive manner. Pak1-dependent phosphorylation of PCBP1 released its binding and translational inhibition from a DICE-minigene. Overexpression of PCBP1 also inhibited the translation of the endogenous L1 cell adhesion molecule mRNA, which contains two DICE motifs in the 3 untranslated region. We also found that Pak1 activation led to an increased nuclear retention of PCBP1, recruitment to the eukaryotic translation initiation factor 4E (eIF4E) promoter, and stimulation of eIF4E expression in a Pak1-sensitive manner. Moreover, mitogenic stimulation promoted Pak1-and PCBP1-dependent alternative splicing and exon inclusion from a CD44 minigene. The alternative splicing functions of PCBP1 were in turn mediated by its intrinsic interaction with Caper ␣, a U2 snRNP auxiliary factor-related protein previously implicated in RNA splicing. These findings establish the principle that a single coregulator can function as a signal-dependent and coordinated regulator of transcription, splicing, and translation. differentiation control element ͉ eukaryotic translation initiation factor 4E ͉ p21-activated kinase 1

Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles

“…These results corroborated earlier studies wherein hnRNP E1 was shown to colocalize with the splice factor SC35 in nuclear speckle (Chkheidze and Liebhaber 2003). In addition, mitogenic stimulation has recently been reported to promote colocalization of hnRNP E1 with SC35 and alternative splicing and exon inclusion from a CD44 minigene (Meng et al 2007). …”

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

“…Our investigation extends the multiple capacity of PCBP1 [43,44] as an E3 ubiquitin ligase adaptor for housekeeping degradation of MAVS [45,46]. Besides, PCBP1 displays some regulatory effects after viral infection ( Figures 3D and 6).…”

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

“…In addition to serine phosphorylation, hnRNP E1 can also be phosphorylated at threonine residues (e.g., threonine 60 and 127) in a Pak1-dependent manner, which also results in decreased association with target mRNAs, as well as nuclear retention (57). Indeed, increased hnRNP E1 threonine phosphorylation and Pak1 phosphorylation/activation were observed in hypoxic HUVEC (see Fig.…”